The present invention relates to compositions and methods for the treatment of HIV infection. More specifically, the invention provides antagonists that inhibit neuropeptide/neuropeptide receptor interactions and methods of administering such antagonists for the treatment of HIV infection.
Several publications are referenced in this application by numerals in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
The neurokinins are a family of neuropeptides that share a common C-terminal region. The main members are Substance P (SP), neurokinin A and neurokinin B. Neurokinin actions are mediated by at least three distinct receptors, NK1, NK2, and NK3. Members of the neurokinin family of neuropeptides modulate functions of cells that are the primary targets for HIV-1 infection, i.e., human T lymphocytes, monocytes and macrophages through interactions with these NK receptors. Substance P (SP), the most extensively studied and potent member of the neurokinin family, is a modulator of neuroimmunoregulation, and in particular, the immune functions of mononuclear phagocytes. SP specifically activates NF-KB, a transcription factor involved in the control of cytokine expression (1,2) and stimulates human peripheral blood monocytes to produce inflammatory cytokines including interleukin 1 (IL-1), IL-6, IL-12 and tumor necrosis factor alpha (TNF-xcex1) (3-5). These cytokines alter HIV expression in T cells and monocytes in vitro (6,7).
SP also plays a role in autocrine regulation in macrophage function (8,9). For example, in the macrophage cell line, P388D1, anti-SP antibody depletion of macrophage secreted SP from the culture resulted in abrogation of SP-increased IL-1 production (8). SP autocrine regulation in monocyte-derived macrophages (MDM) is further evidenced by the presence of specific cell membrane SP receptors (13) and production of SP protein by macrophages (8, 9, 14-17). SP mRNA and protein are present in monocyte/macrophages (M/M) and lymphocytes isolated from human peripheral blood (16, 18). Neurokinin-1 receptor (NK-1R) has also been identified in these cells. Autocrine regulation by SP has also been suggested in other cell types (10-12).
SP and its receptor, NK-1R, are also involved in the modulation of HIV infection both in vivo and in vitro. Azzari et al. (20) observed that HIV-positive children had higher plasma levels of SP compared to HIV-negative children. Annunziata et al. (21) also showed that SP plays a critical role in HIV gp120-induced increases in permeability of rat brain endothelium cultures. Significant SP immunoreactivity has also been observed in HIV gp120 transgenic mouse brain vessels in comparison to non-transgenic mouse brain vessels, suggesting that SP is involved in HIV gp120-induced changes in the vascular component of the blood-barrier (12).
HIV infection continues to be a global issue. While effective anti-HIV treatments are available, it is clear that a need exists of additional beneficial therapeutic agents for combating this disease.
In accordance with the present invention, it has been discovered that SP and the NK receptor family are actively involved in the modulation of HIV infection of human cells. Thus, in a first aspect, methods for inhibiting HIV infection in a patient in need thereof comprising the administration of at least one antagonist specific for the NK receptor family in an effective amount to said patient are provided. An exemplary antagonist has specific binding affinity for the NK1 receptor, and includes without limitation, CP-96,345. Other exemplary antagonists are combined antagonists having binding affinity for the NK1, NK2 and NK3 receptors, such as R-113281.
In yet another aspect of the invention, multiple antagonists at NK receptors may be adminstered in combination. An exemplary combination of antagonists for inhibiting HIV infection comprises both CP-96,345 and R-113281.
The antagonists of the invention may be administered by any route which delivers an effective amount of the antagonist for inhibition of HIV infection. Such routes include without limitation, intravenous administration, parenteral administration, topical administration, and oral administration.
In yet another aspect of the invention, the antagonists of the invention are administered in combination with at least one additional anti-retroviral agent. Additionally, administration of the antagonists of the invention may be combined with the administration of an AIDS vaccine.
Finally, methods for inhibiting HIV infection of a monocyte derived macrophage are also disclosed. In a preferred embodiment, such methods comprise contacting said macrophage with at least one NK receptor antagonist in an amount effective to inhibit HIV entry. NK receptor antagonists may be administered alone or in combination with other NK receptor antagonists or in combination with additional anti-retroviral agents.